Regulation of differentiation and generation of osteoclasts in rheumatoid arthritis

Abstract

Introduction: Rheumatoid arthritis (RA), which affects nearly 1% of the world's population, is a debilitating autoimmune disease. Bone erosion caused by periarticular osteopenia and synovial pannus formation is the most destructive pathological changes of RA, also leads to joint deformity and loss of function,and ultimately affects the quality of life of patients. Osteoclasts (OCs) are the only known bone resorption cells and their abnormal differentiation and production play an important role in the occurrence and development of RA bone destruction; this remains the main culprit behind RA.

Method: Based on the latest published literature and research progress at home and abroad, this paper reviews the abnormal regulation mechanism of OC generation and differentiation in RA and the possible targeted therapy.

Result: OC-mediated bone destruction is achieved through the regulation of a variety of cytokines and cell-to-cell interactions, including gene transcription, epigenetics and environmental factors. At present, most methods for the treatment of RA are based on the regulation of inflammation, the inhibition of bone injury and joint deformities remains unexplored.

Discussion: This article will review the mechanism of abnormal differentiation of OC in RA, and summarise the current treatment oftargeting cytokines in the process of OC generation and differentiation to reduce bone destruction in patients with RA, which isexpected to become a valuable treatment choice to inhibit bone destruction in RA.

Keywords: bone destruction; osteoclasts; regulation of formation and differentiation; rheumatoid arthritis; targeted therapy.

Figure 1

Mechanistic differentiation and function of OC under physiological conditions. OCs are the only osteolytic cells in vivo. It dissolves bone matrix in four steps. The first step is OC adhesion. The integrin and actin microfilaments expressed by OCs allows the cells to closely adhere to the bone surface and form a special cytoskeleton. The second step is OC polarisation, and the OC plasma membrane and cytoskeleton are recombined. The plasma membrane of OCs is divided into four different regions: basal region, wrinkle edge, sealing region and functional secretory region. The third step is degradation of bone matrix. H-ATPase transports H+ to the cavity, allowing the pH of the cavity microenvironment to near a pH of 4-6. This acidic environment loosens the minerals in the bone matrix, and the wrinkle edge also secretes protons and various bone resorption enzymes to degrade organic matter. The fourth step is the removal of degraded products. The degraded bone matrix products are transported from the fold edge to the functional secretory region through endocytosis, and then released extracellularly.

Figure 2

Differentiation regulation of osteoclasts. OC differentiation is a multi-step process, in which cytokines and various cell interactions affect the differentiation of OC from the mononuclear to the terminal state. Among them, autoantibodies directly act on OCs (and their precursors) or cooperate with T and B cells to form a vicious circle. Toll-like receptors (TLR) and Tyro3TK on the surface of OCPs bind to their specific ligands to affect OC differentiation. M1 macrophages secrete many pro-inflammatory cytokines, chemokines and various matrix lyases to activate OCs and aggravate the inflammatory reaction. FLS is the key cell in RA bone destruction. Various pro-inflammatory factors allow it to express RANKL in large quantities. It binds to RANK on the surface of macrophages and OCs and promotes the maturation of OCs through NF- κB signal cascade.

Figure 3

Generation regulation of OCs. When RANK binds to RANKL, on the one hand, RANK recruits TRAF6, activates NF- κB, JNK,p38,c-fos and AP-1; on the other hand, RANK increases the activity of intracellular calcium and activates calcium regulatory neuroenzymes through the Btk/Tec pathway, which promotes the production of phospholipase C (PLC) to mediate the release of intracellular calcium, regulating the activity of CREB and affecting the transcription of various transcription factors.NFATc1 is the main transcription factor in OC differentiation, inducing OC-specific target genes in the nucleus.The activation of NFATc1 is induced by the above two pathways, thus promoting the formation of OC.